70,489 primary care encounters: retrospective analysis of morbidity at a primary care centre in Ireland.

BACKGROUND: While considerable changes are happening in primary care in Ireland and considerable potential exists in intelligence derived from practice-based data to inform these changes, relatively few large-scale general morbidity surveys have been published. AIMS: To examine the most common reasons why people attend primary care, specifically 'reasons for encounter' (RFEs) among the general practice population and among specific demographic groups (i.e., young children and older adults). METHODS: We retrospectively examined clinical encounters (which had a diagnostic code) over a 4-year time period. Descriptive analyses were conducted on anonymised data. RESULTS: 70,489 RFEs consultations were recorded (mean 13.53 recorded RFEs per person per annum) and consultations involving multiple RFEs were common. RFE categories for which codes were most commonly recorded were: 'general/unspecified' (31.6 %), 'respiratory' (15.4 %) and 'musculoskeletal' (12.6 %). Most commonly recorded codes were: 'medication renewal' (6.8 %), 'cough' (6.6 %), and 'health maintenance/prevention' (5.8 %). There was considerable variation in the number of RFEs recorded per age group. 6239 RFEs (8.9 %) were recorded by children under 6 years and 15,295 RFEs (21.7 %) were recorded by adults aged over 70. RFEs recorded per calendar month increased consistently through the study period and there was a marked seasonal and temporal variation in the number of RFEs recorded. CONCLUSIONS: Practice databases can generate intelligence on morbidity and health service utilisation in the community. Future research to optimise diagnostic coding at a practice level and to promote this activity in a more representative sample of practices is a priority.

Does eliminating fees at point of access affect Irish general practice attendance rates in the under 6 years old population? A cross sectional study at six general practices.

With the introduction of free point of access GP care for children aged under six imminent, we sought to determine consultation rates among this group. We interrogated data from practice management systems at six general practices (total patient population 27080). A total of 1931 children aged under six were responsible for 5814 surgery consultations. The mean annual consultation rate was 3.01; 4.91 for GMS' patients, 5.07 for 'Doctor Visit' patients and 2.03 for private patients. Our findings suggest the introduction of free GP care for children under six will considerably increase GP consultations. We also highlight the value of routinely collected general practice data in facilitating health services planning. We estimate that there will be an additional 750,000 GP consultations annually.

Are Irish adult general practice consultation rates as low as official records suggest? A cross sectional study at six general practices.

Accurate data on primary care activity is key to health services planning and reconfiguration. Official data estimate general practice adult consultation rates to be 3.2 visits annually, based on patient self reports. We aim to estimate the consultation rate using practice based data and compare this to official estimates. We interrogated six general practices' information systems and estimated consultation rates based on practice, telephone, domiciliary and out of hours consultations by patients aged 18 years or older. The study population (20,706 patients) was representative of the national population in terms of age and GMS status. The mean consultation rate was 5.17, though this was higher among GMS-eligible patients and among older age groups. Estimates of consultation rates derived from practice based data are likely to be higher than that derived from other approaches. Using multiple sources of data will enhance accuracy of workload estimates and this will benefit service planning.

Muscle fibrillin deficiency in Marfan's syndrome myopathy.

OBJECTIVE: To report a family with Marfan's syndrome in whom a myopathy was associated with respiratory failure; muscle biopsies from affected individuals were examined to determine whether there were abnormalities in fibrillin. METHODS: 21 family members underwent detailed clinical examination, including neurological and pulmonary assessment. Muscle biopsies in the most severely affected cases were immunostained using monoclonal antibodies to specific fibrillin components. Genomic DNA from all 21 members was analysed for mutations in the fibrillin gene, FBN1, on 15q21. RESULTS: 13 individuals had a C4621T base change in exon 37 of the FBN1 gene, which in four cases segregated with muscle weakness or evidence of respiratory muscle dysfunction or both. Their muscle biopsies revealed an abnormality in fibrillin immunoreactivity. CONCLUSIONS: Abnormalities in fibrillin can be detected in muscle biopsies from patients with Marfan's syndrome who have myopathy. This pedigree, with a point mutation in FBN1, also draws attention to the potential for respiratory failure associated with myopathy.

Validation of a simple, rapid, and economical technique for distinguishing type 1 and 2 fibres in fixed and frozen skeletal muscle.

AIMS: To produce a method of distinguishing between type 1 and 2 skeletal muscle fibres that would be more economical and reproducible than the standard ATPase method and be applicable to both fixed and frozen tissue. Because the ATPase method has been accepted as the basis for fibre identification for the past 50 years, the new method should not give significantly different results. METHODS: Isoforms of myosin correlate with isoforms of myofibrillar ATPase and an immunohistochemical (IHC) double labelling protocol was devised using monoclonal antibodies to fast and slow myosin. This required one tissue section rather than four. The results of the two methods were compared by means of morphometric analysis of skeletal muscle biopsies from 20 normal healthy volunteers. RESULTS: There were no significant differences (p = 0.57) in the percentages of type 1 (46% using the IHC method v 48% using ATPase) or type 2 fibres (54% v 52%, respectively). The 2a and 2b subtypes were distinguished easily. Analysis of variance revealed that cross sectional area (mu m(2)), diameter (mu m), form factor, and density of fibre staining (a measure of substrate-enzyme or protein) were all similar. The method worked equally well on fixed material. CONCLUSION: An IHC method based on the fast and slow isoforms of myosin shows no significant differences in fibre type analysis from the standard ATPase method although it provides important advantages because it is applicable to fixed (including archival) material, is economical and reproducible, and yields a permanent preparation.

Enhanced neuronal damage by co-administration of quinolinic acid and free radicals, and protection by adenosine A2A receptor antagonists.

1. Quinolinic acid may be an important endogenous excitotoxin, but its concentrations in brain are low. We have therefore attempted to determine whether its neurotoxicity can be increased by the simultaneous presence of free radicals. 2. Quinolinic acid was injected into the hippocampus of anaesthetized rats at doses of 40 and 80 nmols which produced little neuronal loss, and 120 nmols which produced over 90% neuronal loss. 3. A mixture of xanthine and xanthine oxidase, a known source of free radical reactive oxygen species, also generated little damage alone, but killed over 80% of CA1 neurons when combined with 80 nmols of quinolinic acid. Similarly, the nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP) potentiated the damage produced by quinolinic acid. 4. The glutamate antagonist 5,7-dichlorokynurenic acid prevented the damage produced by 120 nmols of quinolinic acid, but not that produced by quinolinic acid plus xanthine/xanthine oxidase, indicating that damage was not simply the result of free radical enhancement of NMDA receptor activation. 5. Three chemically dissimilar antagonists at adenosine A(2A) receptors prevented the damage caused by quinolinic acid and xanthine/xanthine oxidase or by quinolinic acid plus SNAP. 6. It is concluded that reactive oxygen species can potentiate the neurotoxicity of quinolinic acid. The site of interaction is probably distal to the NMDA receptor. Blockade of adenosine A(2A) receptors can protect against this combined damage, suggesting potential value in the prevention of brain damage.

Antiviral pathway activation in patients with chronic fatigue syndrome and acute infection.

Gene expression of key enzymes in 2 antiviral pathways (ribonuclease latent [RNase L] and RNA-regulated protein kinase [PKR]) was compared in 22 patients with chronic fatigue syndrome (CFS), 10 patients with acute gastroenteritis, and 21 healthy volunteers. Pathway activation in the group of patients with infections differed significantly from that of the other 2 groups, in whom there was no evidence of upregulation. Therefore, assay of activation is unlikely to provide the basis for a diagnostic test for CFS.

The role of kynurenines in the production of neuronal death, and the neuroprotective effect of purines.

The kynurenine metabolic pathway from tryptophan accounts for a large proportion of the metabolism of this amino acid in the brain. Although a major route for the generation of the essential co-factor nicotinamide adenine dinucleotide (NAD), two components of the pathway have marked effects on neurons. Quinolinic acid is an agonist at N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors, while kynurenic acid is an antagonist and, thus, a potential neuroprotectant. The levels of quinolinic acid are known to increase substantially following cerebral insults or infection, and has been most clearly implicated in the AIDS-dementia complex. The actions of quinolinic acid and NMDA show subtle differences, however, which suggest other factors contributing to cell damage. In this article we review the evidence that free radicals may be involved in the neurotoxic effects of quinolinic acid and consider the possibility that quinolinic acid might be involved in Alzheimer's disease. Finally, adenosine receptor ligands can modulate neuronal damage, supporting the view that they may represent suitable targets for the development of novel neuroprotectant drugs for the treatment of Alzheimer's and other neurodegenerative disorders.

Possible mediation of quinolinic acid-induced hippocampal damage by reactive oxygen species.

Several differences exist between quinolinic acid and N-methyl-D-aspartate (NMDA) in the potency and pharmacology of their neurotoxic actions in the brain, suggesting that quinolinic acid may act by mechanisms additional to the activation of NMDA receptors, possibly involving lipid peroxidation. In the present review, studies are considered which have attempted to determine whether free radicals might contribute to the neuronal damage induced by quinolinic acid. Following Injections into the hippocampus of anaesthetised rats, quinolinic acid induced damage is prevented by melatonin, by an action not blocked by the melatonin receptor blocker luzindole. Deprenyl, but not the non-selective monoamine oxidase inhibitor nialamide, also prevent quinolinic acid-induced damage. In vitro, several groups have shown that quinolinic acid can induce lipid peroxidation of brain tissue The results suggest that free radical formation contributes significantly to quinolinic acid-induced damage in vivo.

Muscle changes in the neuroleptic malignant syndrome.

AIMS: To characterise the skeletal muscle changes in the neuroleptic malignant syndrome (NMS). METHODS: Detailed light and ultrastructural examination was carried out on skeletal muscle from three cases of NMS, two associated with recreational drugs (3,4-methlenedioxymethylamphetamine (MDMA, Ecstasy) and lysergic acid diethylamide (LSD)) and one with antipsychotic drugs (fluoxetine (Prozac) and remoxipride hydrochloride monohydrate (Roxiam)). RESULTS: The muscles were grossly swollen and oedematous in all cases, in one with such severe local involvement that the diagnosis of sarcoma was considered. On microscopy, there was conspicuous oedema. In some fascicles less than 10% of fibres were affected whereas in others more than 50% were pale and enlarged. There was a spectrum of changes: tiny to large vacuoles replaced most of the sarcoplasm and were associated with necrosis. A striking feature in some fibres was the presence of contraction bands separating segments of oedematous myofibrils. Severe endomysial oedema was also detectable. There was a scanty mononuclear infiltrate but no evidence of regeneration. CONCLUSIONS: The muscle changes associated with NMS are characteristic and may be helpful in differential diagnosis.

Role of kynurenines in the neurotoxic actions of kainic acid.

The neurotoxic actions of kainic acid can be partly suppressed by antagonists acting at N-methyl-D-aspartate (NMDA) receptors. The present study examined the possible role of endogenous components of the kynurenine pathway to this phenomenon. Administration of kainate (2 nmols) into the hippocampus of anaesthetized rats produced damage in the CA1 and CA3 regions. The involvement of NMDA receptors was confirmed by the ability of dizocilpine (1 mg kg(-1)) to reduce cell loss in the CA1 region from 92 to 42%. The co-administration of m-nitrobenzoylalanine (20 nmols into the hippocampus), an inhibitor of kynurenine hydroxylase and kynureninase, together with a systemic injection of the compound (100 mg kg(-1), i.p.), afforded some protection against kainate, reducing cell loss from 91 to 48%. Protection was not exerted against damage by quinolinic acid or NMDA, excluding a direct interaction between m-nitrobenzoylalanine and NMDA receptors. The protective effect of m-nitrobenzoylalanine was not prevented by glycine, which would be expected to reverse protection caused by an elevation in the levels of endogenous kynurenic acid, arguing against a major role for increased levels of kynurenic acid. The results indicate that inhibition of the kynurenine pathway offers protection against kainate-induced damage. One possible mechanism for the protection is that an increased production of quinolinic acid in the brain, possibly from glial cells and macrophages activated by the initial kainate insult, normally contributes to the local activation of NMDA receptors and thus to kainate-induced cerebral insults. This generation of endogenous quinolinic acid would be suppressed by m-nitrobenzoylalanine.

Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenyl.

1. There are differences between the excitotoxic actions of quinolinic acid and N-methyl-D-aspartate (NMDA) which suggest that quinolinic acid may act by mechanisms additional to the activation of NMDA receptors. The present study was designed to examine the effect of a potent antioxidant, melatonin, and the potential neuroprotectant, deprenyl, as inhibitors of quinolinic acid-induced brain damage. Injections were made into the hippocampus of anaesthetized rats, which were allowed to recover before the brains were taken for histology and the counting of surviving neurones. 2. Quinolinic acid (120 nmols) induced damage to the pyramidal cell layer, which was prevented by the co-administration of melatonin (5 nmols locally plus 2x20 mg kg(-1) i.p.). This protective effect was not prevented by the melatonin receptor blocker luzindole. Neuronal damage produced by NMDA (120 nmols) was not prevented by melatonin. 3. Quinolinic acid increased the formation of lipid peroxidation products from hippocampal tissue and this effect was prevented by melatonin. 4. Deprenyl also prevented quinolinic acid-induced damage at a dose of 50 nmols but not 10 nmols plus 2x1.0 mg kg(-1) i.p. The non-selective monoamine oxidase inhibitor nialamide (10 and 50 nmols plus 2x25 mg kg(-1)) did not afford protection. 5. The results suggest that quinolinic acid-induced neuronal damage can be prevented by a receptor-independent action of melatonin and deprenyl, agents which can act as a potent free radical scavenger and can increase the activity of endogenous antioxidant enzymes respectively. This suggests that free radical formation contributes significantly to quinolinic acid-induced damage in vivo.

Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome.

Patients with the chronic fatigue syndrome (CFS) complain consistently of delay in recovery of peripheral muscle function after exercise. The purpose of this study was to try to confirm this observation. A fatiguing exercise test was carried out on the quadriceps muscle group of ten patients and ten control subjects. The test consisted of 18 maximum voluntary contractions (MVCs) with a 50% duty cycle (10 s contraction, 10 s rest), and the force generated by each contraction was recorded using a KinCom dynamometer. This was followed by a recovery phase lasting 200 min in which quadriceps strength was evaluated at increasing intervals, and a follow-up session at 24 h post-exercise involving three 10 s MVCs. Throughout the exercise period, the MVCs obtained from the control group were significantly higher than those of the patient group (P = 0.006), but both groups showed a parallel decline in force over the 18 contractions, in keeping with a similar endurance capacity. Recovery was prolonged in the patient group, however, with a significant difference compared to initial MVCs being evident during the recovery phase after exercise (P = 0.001) and also at 24 h (P < 0.001). In contrast, the control group achieved MVCs which were not significantly different from initial values during the recovery phase, and maintained these at 24 h. These findings support the clinical complaint of delayed recovery after exercise in patients with CFS.

Genomic and template RNA transcription in a model of persistent enteroviral infection.

Enteroviruses have been implicated in persistent infections of the nervous system and in certain paralytic motor neuron syndromes. Enteroviral persistence may depend on defective transcription, resulting in the abnormal production of equal amounts of genomic and template RNA strands rather than the normal ratio of 60-100:1. An in vitro model of a persistent coxsackie virus in human skeletal muscle cells was investigated using in situ hybridisation and a semiquantitative parallel, complementary, reverse transcriptase polymerase chain reaction. The ratio of genomic to template RNA was found to be approximately 60:1. We conclude that enteroviral persistence in this in vitro model is not dependent on altered transcription. In vivo, other viral and host factors should be considered.

Adenocarcinoma of the anal glands.

Adenocarcinoma of the anal glands is very rare but it is an important lesion to recognise as with early diagnosis, it has an excellent prognosis. Because it involves the submucosa widely and penetrates the mucosa late, it can be mistaken for metastatic gastrointestinal carcinoma, or tumour arising in sinuses and fistulae. Two cases, in a 44 year old man and a 73 year old woman, which illustrate the typical features are reported, in one of which the diagnosis was missed originally. In situ neoplastic change of the associated anal glands and secretion of mucin lacking O-acetyl groups are useful pointers.

Search for picornaviruses at onset of inflammatory myopathy.

Picornaviruses may not play a role as persistent agents in the inflammatory myopathies, but it is still thought likely that they may act as triggers of an autoimmune process. Forty one muscle biopsy specimens, taken from three weeks to six months (mean four months) after onset, were examined using three different picornaviral primers and PCR. Moderate to severe disease activity was evident in all specimens. The results were compared with those of 18 biopsy specimens examined later in the disease course, and with specimens from 27 patients with non-inflammatory myopathies. All results were negative. Thus, even as early as three weeks after clinical disease appears, picornaviruses are not detectable in these disorders.

Mouse inoculation studies reveal no transmissible agent in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) resembles the spongiform encephalopathies in its dual pattern of inherited and sporadic cases, its uniform prevalence in different populations, its late onset (suggestive of a long incubation period) and its pathological picture of neuronal degeneration without inflammation. There is a well-established protocol for primary transmission of scrapie and related diseases to mice. Using this, we inoculated four longlived, inbred, mouse strains with cord material fresh-frozen within three hours of death, from a case of ALS or a control case. No motor neuron loss, gliosis or tract demyelination was found in the experimental group. Fifty per cent of each group were observed for more than 600 days. Two types of lesions were found in these animals at death: widespread foci of white matter vacuolation and bilateral thalamic mineral deposits. They were present in the control group at the same incidence and severity as in the experimental group and were thus considered to represent an age-related change. Attention is drawn to them because they have been claimed as significant when found in a transgenic model of spongiform encephalopathy. The results of our carefully-controlled experiment suggest that it is unlikely that ALS is caused by a scrapie-like agent capable of transmission to mice.